PROJECT SUMMARY Patients with Parkinson?s disease (PD) experience progressive motor impairments that lead to severe disability. The motor impairments of PD are associated with abnormal neuronal activity in the basal ganglia, a group of brain structures involved in movement planning and execution. The long-term goal of our research is to elucidate how the abnormal activity of the basal ganglia relates to the motor deficits in PD, with the goal of developing novel therapies to treat parkinsonism with improved specificity and fewer unwanted side effects. The proposed studies are focused on the external segment of the globus pallidus (GPe), a key structure in the basal ganglia circuitry. Traditionally, the GPe was thought to be composed of a single neuron type; it is now established that this nucleus contains different types of neurons that can be classified based on their projection targets (?upstream? to the striatum, or ?downstream? to the subthalamic nucleus or internal pallidum). In rodent models of PD, there is evidence that PD-related abnormalities occur selectively in specific types of GPe neurons, raising the possibility that different GPe neuron populations might make distinct contributions to the normal and pathological roles of the GPe. However, the translational relevance of these findings is limited by functional and anatomical differences between the rodent and primate GPe. Our experiments will define functional differences between classes of GPe neurons in normal rhesus monkeys and in monkeys rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys are an excellent animal model for studying PD-related changes in brain activity, because their basal ganglia and connected brain structures closely resemble those in humans, and because MPTP-treated monkeys show the majority of the motor impairments seen in PD patients. We will use electrophysiological in vivo recordings to evaluate differences in the firing rates and patterns of GPe-upstream and GPe-downstream neurons. The projections of individual GPe neurons will be identified by their antidromic responses to electrical stimulation of the target structures (aim 1). To determine how GPe neurons modulate the activity in the striatum, subthalamic nucleus or internal pallidum, we will selectively silence GPe axonal terminals in each of these nuclei, using optogenetic methods. We will also determine whether selective silencing of GPe terminals alters PD-motor impairments in monkeys (aim 2). Finally, we will use histologic techniques to identify proteins whose expression reveals specific GPe neuron projection patterns (aim 3). Our studies will begin to determine how the activities of primate GPe neuron subtypes differ, how they regulate the activity in other basal ganglia neurons in the normal and parkinsonian states, and whether they are involved in the pathophysiology of parkinsonism. The knowledge gained from these studies is significant, as it may enable us to develop new treatments for PD that harness functional and anatomical differences of GPe neuron types.